Bottom Line:
Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established.Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired.These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model.

Affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

ABSTRACT

Objective: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity.

Conclusions: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.

Mentions:
As previously reported (28), ob/ob mice developed grossly steatotic livers with macrosteatosis and microsteatosis that weighed four times more than livers from lean littermates (Table 1) and accumulated nearly five times as much TAG (Fig. 2A and B). In ob/ob-Gpat1−/− mice, the lack of Gpat1 reduced liver weight by 28% and hepatic TAG content by 59%, evidenced by the absence of large lipid droplets. In ob/ob livers, the lipogenic genes fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) were increased 4- and 6.4-fold, respectively. However, neither Fasn and Scd1 nor transcription factors that regulate lipogenesis, SREBP1 (Srebf1) and ChREBP (Mlxipl), were affected by the lack of Gpat1 (supplementary Fig. 2A). Similarly, protein expression of the mature form of SREBP1 was not affected by the absence of Gpat1 (supplementary Fig. 2B). The expression of genes related to β-oxidation was not altered (supplementary Fig. 2C). Combined, these data suggest that Gpat1 appeared to be a major SREBP1 target gene causing hepatic steatosis in ob/ob mice.

Mentions:
As previously reported (28), ob/ob mice developed grossly steatotic livers with macrosteatosis and microsteatosis that weighed four times more than livers from lean littermates (Table 1) and accumulated nearly five times as much TAG (Fig. 2A and B). In ob/ob-Gpat1−/− mice, the lack of Gpat1 reduced liver weight by 28% and hepatic TAG content by 59%, evidenced by the absence of large lipid droplets. In ob/ob livers, the lipogenic genes fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) were increased 4- and 6.4-fold, respectively. However, neither Fasn and Scd1 nor transcription factors that regulate lipogenesis, SREBP1 (Srebf1) and ChREBP (Mlxipl), were affected by the lack of Gpat1 (supplementary Fig. 2A). Similarly, protein expression of the mature form of SREBP1 was not affected by the absence of Gpat1 (supplementary Fig. 2B). The expression of genes related to β-oxidation was not altered (supplementary Fig. 2C). Combined, these data suggest that Gpat1 appeared to be a major SREBP1 target gene causing hepatic steatosis in ob/ob mice.

Bottom Line:
Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established.Despite the reduction in hepatic lipids, fasting glucose and insulin concentrations did not improve, and insulin tolerance remained impaired.These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model.

Affiliation:
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

ABSTRACT

Objective: Hepatic steatosis is strongly associated with insulin resistance, but a causal role has not been established. In ob/ob mice, sterol regulatory element binding protein 1 (SREBP1) mediates the induction of steatosis by upregulating target genes, including glycerol-3-phosphate acyltransferase-1 (Gpat1), which catalyzes the first and committed step in the pathway of glycerolipid synthesis. We asked whether ob/ob mice lacking Gpat1 would have reduced hepatic steatosis and improved insulin sensitivity.

Conclusions: These results suggest that decreasing hepatic steatosis alone does not improve insulin resistance, and that factors other than increased hepatic DAG and TAG contribute to hepatic insulin resistance in this genetically obese model. They also show that the SREBP1-mediated induction of hepatic steatosis in ob/ob mice requires Gpat1.